The treatment of Takayasu arteritis (TAK) with glucocorticoids (GCs)-sparing agents is an unmet need. About 30-50% patients relapse during GC tapering even under tocilizumab or TNF inhibitor treatment, underscoring the need to explore more effective agents. Th1 and Th17 are predominant CD4+ T cell subtypes in  the vascular lesion of Takayasu arteritis. Howelver, Th17 cytokines persisted even after GC treatment, suggesting a critical role of IL17 in this disorder. Secukinumab,  a human anti-IL-17A monoclonal antibody, showed treatment effect in giant cell arteritis according to a randomized controlled study. A small-scale study also showed that secukinumab had similar effects to tumor necrosis factors in refractory TAK, but the sample was small and the follow-up period was short. Thus, the present study aimed to evaluate the treatment effect of secukinumab in a two year period and also to explore patients who would benefit most from secukinumab.

Study design: This is a single center, prospective study conducted in the Department of Rheumatology, Zhongshan Hospital, Fudan University. The inclusion criteria were: 1) diagnosed as TAK according to 2022 ACR/European Alliance of Associations for Rheumatology (EULAR) ; 2) in active status (NIH criteria score ≥2). The exclusion criteria included: 1) active infections such as hepatitis or tuberculosis; 2) a malignancy; 3) concurrent autoimmune disease; 4) concurrent ulcerative colitis. Eligible patients were treated with GC and methotrexate combined with either secukinumab (SEC group) or adalimumab (ADA group). 

Intervention: The secukinumab dose was 150 mg by subcutaneous injection once per week from baseline to week 4, and every 4 weeks thereafter. The adalimumab dose was 40 mg by subcutaneous injection every 2 weeks. For treatment-naïve patients, the initial GC dose was 0.6–0.8 mg/kg/day. For patients with refractory TAK, the initial GC dose was maintained at the same level as the time of disease relapse. During follow-up, the GC dose was tapered gradually according to a predefined scheme. The target dose is 10mg/day, 7.5mg/day and 5mg/day at 6, 12 and 24 months respectively. 

Outcomes: The primary endpoint is sustained remission (SR) at 12 and 24 months. Secondary endpoints included complete remission (CR) ar 6, 12, and 12 months, relapse and cumulative relapse rate in 24 months; GCs tapering; imaging changes; changes of inflammatory markers and immune cells, and safety. 

Definations of Outcomes: CR was defined as 1) no systemic symptoms, 2) no new or worsened vascular symptoms or signs, 3) ESR was normal; 4) no new vascular lesions or worsened vascular lesions; and 5) GC tapering to a target dose for ≥4 weeks. SR was defined as persistent CR to 12 or 24 months with GC tapering to a target dose. Relapse was evaluated according to EULAR recommendations. 

Statistical analysis: The treatment effect was mainly analyzed in the per-protocol analysis. Patients withdrew due to disease flare or severe side effects will be assessed as “ineffective”. The prospensity score matching was performed to control confounders including age, sex, disease duration, treatment status, NIH score, and vascular imaging type. The subgroup analysis was analyzed in treatment-naive or treatment-refractory patients separately. Competing-risk analysis was performed to assess the cumulative relapse in the two groups with treatment discontinuation as a competing event. A global test was conducted to evaluate the suppression effect on multiple inflammatory parameters including platelet count, ESR, CRP, C3, C4, and IL-6 within 6 months. Multivariate logistic regression analysis was performed to explore the predictive factors for sustained remission at 12 months. 

Between 1 December 2021 to 1 January 2024, 104 patients (secukinumab group: 46; adalimumab group: 58) were enrolled, with average age as 32.73 (SD 11.19) years, 90 (86.54%) female and 54 (51.92%) treatment-naive. 

Approximately 40% of patients attained SR by month 12; however, but there was no significant difference between the groups (SEC: 37.78% vs. ADA 41.18%, P = 0.84, OR 1.45 [0.60, 3.53]). Similarly, no significant difference was observed between the two groups in the rate of SR at 24 months. No statistical difference was observed either in treatment-naive or treatment-refractory patients separately. The adalimumab group showed a numerically higher 6-month CR rate (55.17% vs. 41.30%; OR 2.1, 95% CI 0.93–4.81; P=0.07), but with no significant difference after propensity-score matching. 

The relapse rate was also comparable (ADA: 19.05% vs. SEC 33.33%, P = 0.15). The first time to relapse were 17.00 ± 6.78 vs. 16.38 ± 6.63 months (P = 0.86). However, the competing- risk analysis demonstrated that the adalimumab group exhibited a trend toward a relatively lower cumulative incidence of relapse (10.11% vs. 26.16%, HR 0.41 [95% CI 0.18−0.90], P = 0.07). 

No significant differences were found in the percentage of patients who achieved GC ≤10 mg/day at 6 months, ≤7.5 mg/day at 12 months, ≤5 mg/day at 24 months between the SEC group and ADA group (6 months: 58.69% vs. 62.07%, P = 0.84; 12 months: 53.66% vs. 59.57%, P = 0.67; 24 months: 58.82% vs. 60.61%, P = 1.00). 

The incidence of different imaging alterations were comparable. 

In cellular and molecular levels, the ADA group had a stronger global effect in suppressing inflammatory markers, while the SEC group demonstrated a persistent inhibition in B cell ratio. 

Patients achieved SR at 12 months had differential baseline immune features between two treatment groups. A relaltively higher baseline B cell ratio was a predictor of SR in the SEC group (CD19+ B cell cut-off value : ≥ 15.7%, area under ROC curve: 0.71 [95% CI: 0.56-0.86], sensitivity 76.47%, specificity 72.42%). 

When stratifying patients into B cell ratio-high subgroup and B cell ratio-low subgroup based on the ratio 15.7%, the SEC group achieved relatively higher CR rate and sustained CR rate at 12 months (13/18 [72.22%] vs. 4/11 [36.36%], OR 1.99 [95% CI: 0.86-4.57], P = 0.12) in the B cell ratio-high (>15.7%) subgroup. However, in the B cell ratio-low subgroup, the ADA group attained significantly higher CR and sustained CR rate at 12 months (19/36 [52.78%] vs. 5/23 [21.74%], OR 1.65 [95% CI: 1.10-2.49], P = 0.03; 17/36 [47.22%] vs. 4/23 [17.39%], OR 1.56 [95% CI: 1.09-2.25], P = 0.03).

The most common side effect was infection in both groups. The rate of severe side effects were 1.7% in the ADA group and 4.35% in the SEC group. Cancer developed in one patient in each group during the treatment. 

Overall, secukinumab has comparable efficacy to adalimumab in TAK.  Adalimumab shows rapid effect in inflammation suppression and may be more effective in preventing disease replase in TAK in a long term. 

Impact on clinical practices:

1. Secukinumab might be another GC-sparing option for TAK.

2. Baseline B-cell levels may serve as a potential biomarker for targeted therapy selection between IL-17 and TNF inhibitors.